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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concept of pharmacomechanical coupling, introduced 30 years ago to account for physiological mechanisms that can regulate contraction of smooth muscle independently of the membrane potential, has since been transformed from a definition into what we now recognize as a complex of well-defined, molecular mechanisms. The release of Ca2+ from the SR by a chemical messenger, InsP3, is well known to be initiated not by depolarization, but by agonist-receptor interaction. Furthermore, this G-protein-coupled phosphatidylinositol cascade, one of many processes covered by the umbrella of pharmacomechanical coupling, is part of complex and general signal transduction mechanisms also operating in many non-muscle cells of diverse organisms. It is also clear that, although the major contractile regulatory mechanism of smooth muscle, phosphorylation/dephosphorylation of MLC20, is [Ca2+]-dependent, the activity of both the kinase and the phosphatase can also be modulated independently of [Ca2+]i. Sensitization to Ca2+ is attributed to inhibition of SMPP-1M, a process most likely dominated by activation of the monomeric GTP-binding protein RhoA that, in turn, activates Rho-kinase that phosphorylates the regulatory subunit of SMPP-1M and inhibits its myosin phosphatase activity. It is likely that the tonic phase of contraction activated by a variety of excitatory agonists is, at least in part, mediated by this Ca(2+)-sensitizing mechanism. Desensitization to Ca2+ can occur either through inhibitory phosphorylation of MLCK by other kinases or autophosphorylation and by activation of SMPP-1M by cyclic nucleotide-activated kinases, probably involving phosphorylation of a phosphatase activator. Based on our current understanding of the complexity of the many cross-talking signal transduction mechanisms that operate in cells, it is likely that, in the future, our current concepts will be refined, additional mechanisms of pharmacomechanical coupling will be recognized, and those contributing to the pathologenesis diseases, such as hypertension and asthma, will be identified.
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PMID:Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases. 1008 10

The growth-promoting effect of mechanical stress on vascular smooth muscle cells (VSMCs) has been implicated in the progress of vascular disease in hypertension. Extracellular signal-regulated kinases (ERKs) have been implicated in cellular responses, such as vascular remodeling, induced by mechanical stretch. However, it remains to be determined how mechanical stretch activates ERKs. The cytoskeleton seems the most likely candidate for force transmission into the interior of the cell. Therefore, we examined (1) whether the cytoskeleton involves mechanical stretch-induced signaling, (2) whether Rho is activated by stretch, and (3) whether Rho mediates the stretch-induced signaling in rat cultured VSMCs. Mechanical stretch activated ERKs, with a peak response observed at 20 minutes, followed by a significant increase in DNA synthesis. Treatment with the ERK kinase-1 inhibitor, PD98059, inhibited the stretch-induced increase in DNA synthesis. Cytochalasin D, which selectively disrupts the network of actin filaments, markedly inhibited stretch-induced ERK activation. In the control state, RhoA was observed predominantly in the cytosolic fraction, but it was translocated in part to the particulate fraction in response to mechanical stretch. Botulinum C3 exoenzyme, which inactivates Rho p21 (known to participate in the reorganization of the actin cytoskeleton), attenuated stretch-induced ERK activation. Inhibition of Rho kinase (p160ROCK) also suppressed stretch-induced ERK activation dose dependently. Our results suggest that mechanotransduction in VSMCs is dependent on intact actin filaments, that Rho is activated by stretch, and that Rho/p160ROCK mediates stretch-induced ERK activation and vascular hyperplasia.
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PMID:Mechanotransduction of rat aortic vascular smooth muscle cells requires RhoA and intact actin filaments. 1040 Sep 5

We here review mechanisms that can regulate the activity of myosin II, in smooth muscle and non-muscle cells, by modulating the Ca2+ sensitivity of myosin regulatory light chain (RLC) phosphorylation. The major mechanism of Ca2+ sensitization of smooth muscle contraction and non-muscle cell motility is through inhibition of the smooth muscle myosin phosphatase (MLCP) that dephosphorylates the RLC in smooth muscle and non-muscle. The active, GTP-bound form of the small GTPase RhoA activates a serine/threonine kinase, Rho-kinase, that phosphorylates the regulatory subunit of MLCP and inhibits phosphatase activity. G-protein-coupled release of arachidonic acid may also contribute to inhibition of MLCP acting, at least in part, through the Rho/Rho-kinase pathway. Protein kinase C(s) activated by phorbol esters and diacylglycerol can also inhibit MLCP by phosphorylating and thereby activating CPI-17, an inhibitor of its catalytic subunit; this mechanism is independent of the Rho/Rho-kinase pathway and plays only a minor, transient role in the G-protein-coupled mechanism of Ca2+ sensitization. Ca2+ sensitization by the Rho/Rho-kinase pathway contributes to the tonic phase of agonist-induced contraction in smooth muscle, and abnormally increased activation of myosin II by this mechanism is thought to play a role in diseases such as high blood pressure and cancer cell metastasis.
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PMID:Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. 1063 96

Angiotensin II (Ang II) is now believed to play a critical role in the pathogenesis of hypertrophy and/or hyperplasia of vascular smooth muscle cells (VSMCs). Several G(i)- and G(q)-coupled receptors, including the Ang II type 1 (AT(1)) receptor, activate Rho and Rho-associated kinase in Swiss 3T3 cells and cardiac myocytes. However, little is known about the role of Rho-kinase in Ang II-induced vascular hypertrophy in VSMCs. In the present study, we explored the role of Rho and Rho-kinase in Ang II-induced protein synthesis in VSMCs. In unstimulated cells, RhoA was observed predominantly in the cytosolic fraction, but it was translocated in part to the particulate fraction in response to Ang II (100 nmol/L). This effect was completely blocked by the AT(1) receptor blocker candesartan but not by the Ang II type 2 (AT(2)) receptor antagonist PD123319. Botulinum C(3) exoenzyme, which inactivated RhoA, attenuated Ang II-induced [(3)H]leucine incorporation. The specific Rho-kinase inhibitor, Y-27632, dose-dependently abolished Ang II-induced protein synthesis and also suppressed Ang II-induced c-fos mRNA expression. On the other hand, Y-27632 had no effect on Ang II-stimulated phosphorylation of p70 S6 kinase and extracellular signal-regulated kinase 1/2, which are reported to be involved in Ang II-induced protein synthesis, nor had it any effect on the Ang II-induced phosphorylation of PHAS-I, a heat- and acid-stable eIF-4E-binding protein. The phosphorylation of PHAS-I is regulating for translation initiation. These observations suggest that the Rho, Rho-kinase, and c-fos pathways may play a role in Ang II-induced hypertrophic changes of VSMCs through a novel pathway.
Hypertension 2000 Jan
PMID:Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells. 1064 17

Angiotensin II (Ang II)-induced phospholipase D (PLD) activity is greater in aortic smooth muscle from spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto rats (WKY). Whether and how this signaling pathway is altered in preglomerular microvascular smooth muscle cells (PGSMCs), a cell type that may participate in genetic hypertension, is unknown. The goals of the present study were to determine in SHR and WKY PGSMCs the following: (1) whether Ang II induces PLD activity; (2) whether the effect of Ang II on PLD activity is greater in SHR; (3) which PLD isoform is stimulated by Ang II; (4) what signaling pathway mediates Ang II-induced PLD stimulation; and (5) whether the signaling pathways mediating Ang II-induced PLD activity are different in SHR and WKY. The EC(50) for Ang II-induced PLD stimulation in SHR was 10-fold lower than the EC(50) in WKY, and both were inhibited by L-158,805, an AT(1) antagonist. Inhibitors of phosphoinositol-3-kinase and protein kinase C did not block Ang II-induced PLD activity in SHR and WKY PGSMCs. Catalytically-inactive constructs of PLD2 and RhoA, but not PLD1, ADP ribosylation factor 1 (ARF1), ARF6, or ADP ribosylation factor nucleotide exchange factor (ARNO) blocked Ang II-induced PLD activity in SHR and WKY PGSMCs. Brefeldin A completely blocked Ang II-induced PLD activity in SHR but only slightly reduced Ang II-induced PLD activity in WKY PGSMCs. Therefore, we conclude that in PGSMCs, the effect of Ang II on PLD activity is (1) greater in SHR; (2) mediated by AT(1) receptors signaling to PLD2; (3) transduced primarily by Rho proteins; and (4) inhibited in SHR by brefeldin A.
Hypertension 2001 Feb
PMID:Angiotensin II signaling to phospholipase D in renal microvascular smooth muscle cells in SHR. 1123 Mar 48

Hypertension, the result of a sustained increase in vascular peripheral resistance, is partly due to vascular remodeling and increased vasoconstrictor sensitivity. Stimulation of heterotrimeric G-protein-coupled receptors by various contractile agonists activates intracellular signaling molecules to result in an increase in cytosolic Ca++ and the subsequent phosphorylation of myosin light chain by Ca++/calmodulin-dependent myosin light chain kinase. Additionally, a portion of alpha-adrenergic, serotonergic, and endothelin-1-induced contraction is partially mediated by the calcium-independent activation of the small G-protein RhoA and of a downstream target, Rho-kinase. Isolated arteries from hypertensive animals have been shown to have an increased contractile sensitivity to various agonists and to exhibit evidence of remodeling. Recent data suggest that some of these vascular changes may be mediated by increased activity of RhoA/Rho-kinase, potentially introducing a novel therapeutic approach for the treatment of hypertension.
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PMID:RhoA/Rho-kinase, vascular changes, and hypertension. 1127 96

We have previously shown that the function of the small G protein Rho is required for vascular smooth muscle cell proliferation and migration. We hypothesized that changes in Rho or Rho signaling might contribute to enhanced vascular proliferative responses associated with hypertension. Western blot analysis revealed that total RhoA expression was approximately 2-fold higher in aortas, tail arteries, and aortic smooth muscle cells (ASMCs) obtained from adult male spontaneously hypertensive rats (SHR) compared with those from Wistar Kyoto rats (WKY). An increase in active GTP-bound RhoA was detected in aortic homogenates by affinity precipitation with the RhoA effector rhotekin and by examining RhoA-[(35)S]GTPgammaS binding. RhoA protein and activity were also increased in vessels from rats treated with N-nitro-L-arginine methyl ester to increase blood pressure. Thrombin-stimulated RhoA activation was also significantly greater in ASMCs from SHR. As a functional correlate of these changes in Rho signaling, thrombin-stimulated DNA synthesis was enhanced in tail arteries and ASMCs from SHR. Expression of the cyclin-dependent kinase inhibitor p27(Kip1) was decreased by two thirds in SHR, and this decrease was mimicked in ASMCs by expression of a constitutively active (GTPase-deficient) mutant of RhoA. Wortmannin (10 nmol/L) fully inhibited the decrease in p27(Kip1) induced by RhoA, and a membrane-targeted catalytic subunit of phosphatidylinositol-3 kinase (PI3K [p110(CAAX)]) decreased p27(Kip1) expression, suggesting that RhoA signals through PI3K. These data provide evidence that RhoA brings about changes in DNA synthesis through reduced expression of p27(Kip1), mediated in part via PI3K, and suggest that increases in RhoA expression and activity contribute to the enhanced vascular responsiveness observed in hypertension.
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PMID:Increased expression and activity of RhoA are associated with increased DNA synthesis and reduced p27(Kip1) expression in the vasculature of hypertensive rats. 1155 35

Recent studies from our laboratory have shown that insulin stimulates myosin-bound phosphatase (MBP) in vascular smooth muscle cells (VSMCs) by decreasing site-specific phosphorylation of the myosin-bound subunit (MBS) of MBP via nitric oxide/cGMP-mediated Rho/Rho kinase inactivation. Here we tested potential interactions between Rho kinase and insulin signaling pathways. In control VSMCs, insulin inactivates ROK-alpha, the major Rho kinase isoform in VSMCs, and inhibits thrombin-induced increase in ROK-alpha association with the insulin receptor substrate-1 (IRS-1). Hypertension (in spontaneous hypertensive rats) or expression of an active RhoA(V14) up-regulates Rho kinase activity and increases ROK-alpha/IRS-1 association resulting in IRS-1 serine phosphorylation that leads to inhibition of both insulin-induced IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3-kinase) activation. In contrast, expression of dominant negative RhoA or cGMP-dependent protein kinase type I alpha inactivates Rho kinase, abolishes ROK-alpha/IRS-1 association, and potentiates insulin-induced tyrosine phosphorylation and PI3-kinase activation leading to decreased MBS(T695) phosphorylation and decreased MBP inhibition. Collectively, these results suggest a novel function for ROK-alpha in insulin signal transduction at the level of IRS-1 and potential cross-talk between cGMP-dependent protein kinase type I alpha, Rho/Rho kinase signaling, and insulin signaling at the level of IRS-1/PI3-kinase.
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PMID:Active Rho kinase (ROK-alpha ) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. 1173 94

NO induces vasodilation through cGMP-dependent protein kinase--dependent and --independent mechanisms. A recent study demonstrated that recombinant cGMP-dependent protein kinase can phosphorylate the small G protein, RhoA, thus inhibiting its activity. Additionally, sodium nitroprusside was found to reverse the phenylephrine-induced translocation of RhoA, which is further indicative of the inhibition of RhoA activity. RhoA is known to be involved in the Ca(2+) sensitization of vascular smooth muscle through the actions of one of its downstream effectors, Rho-kinase. This study examined whether NO endogenously induces the relaxation of intact rat aorta via the inhibition of the Rho-kinase--mediated Ca(2+)-sensitizing pathway. Endogenous Rho-kinase inhibitor activity was inhibited by the selective compound Y-27632. Treatment of endothelium-intact rat aorta with Y-27632 (1 micromol/L) resulted in an attenuation of maximal force generated in response to phenylephrine. In endothelium-denuded rings, however, 1 micromol/L Y-27632 was ineffective at inhibiting the phenylephrine-induced contraction. Additionally, 1 micromol/L Y-27632 was significantly less effective at inhibiting the phenylephrine-induced contraction of endothelium-intact rings in the presence of inhibitors of NO synthase or guanylate cyclase (N(omega)-nitro-L-arginine and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, respectively). Interestingly, sodium nitroprusside restored the ability of 1 micromol/L Y-27632 to attenuate phenylephrine-induced contraction. Rho-kinase inhibition was also found to increase the sensitivity of the endothelium-denuded aorta to sodium nitroprusside. These data demonstrate that NO inhibits Rho-kinase activity in the intact rat aorta, supporting the hypothesis that endogenous NO-mediated vasodilation occurs through the inhibition of Rho-kinase constrictor activity in the intact rat aorta.
Hypertension 2002 Feb
PMID:Nitric oxide induces dilation of rat aorta via inhibition of rho-kinase signaling. 1188 86

Cell adhesion to fibronectin results in formation of actin stress fibres and focal adhesions. In fibroblasts, this response requires two co-operative signals provided by interactions of the RGD sequence with alpha5beta1 integrin and the heparin-binding domain II (Hep II) domain with syndecan-4. Within Hep II, this activity was mapped to repeat III13 and to the peptide FN-C/H-V(WQPPRARITGY, repeat III14). We previously described that the synthetic heparin-binding peptide/III5 (HBP/III5) (WTPPRAQITGYRLTVGLTRR, repeat III5) binds heparin and mediates cell adhesion via chondroitin sulphate proteoglycans. We have now studied whether HBP/III5 co-operates with alpha5beta1 and drives a full cytoskeletal response in melanoma cells. SKMEL-178 cells attached and spread on the RGD-containing FNIII7-FNIII10 (FNIII7-10) fragment, but did not form stress fibres or focal adhesions. Co-immobilization of HBP/III5 with FNIII7-10 or adding soluble HBP/III5 to cells prespread on FNIII7-10, effectively induced these structures. Cell transfection with dominant-negative N19RhoA, a member of the small GTPase family, abolished the HBP/III5 effect. Both chondroitinase and heparitinase diminished focal adhesions, indicating that both types of proteoglycans bound HBP/III5 in melanoma cells. We have mapped the active sequence of HBP/III5 to YRLTVGLTRR, which is a novel sequence in fibronectin with focal-adhesion-promoting activity. The last two arginine (R) residues of this sequence are required for activity, since their replacement by alanine completely abrogated the HBP/III5 cytoskeletal effect. Moreover, this sequence is also active in the context of large fibronectin fragments. Our results establish that the Hep III region provides co-operative signals to alpha5beta1 for the progression of the cytoskeletal response and that these include activation of RhoA.
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PMID:A synthetic peptide from the heparin-binding domain III (repeats III4-5) of fibronectin promotes stress-fibre and focal-adhesion formation in melanoma cells. 1251 80


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